Acute myeloid leukemia (AML) affected ~14,600 new patients in 2013 in the US and caused over 10,000 deaths, primarily in older adults. The current chemotherapy regimen, a combination of cytarabine (AraC) and anthracyclines such as daunorubicin (DNR), has resulted in 5-year survival rates of only 30-40% (less than 10% in patients over 60 years old). The principal cause of treatment failure is chemotherapy resistance, despite an initial complete remission rate of 65%. The long-term goal of this STTR project is to develop a new drug for AML treatment that shows high efficacy in relapsed or refractory AML. F10 is a rationally designed molecule incorporating5-fluoro-2'-deoxyuridine-5'-O-monophosphate (FdUMP), the active metabolite of 5-fluorouracil (5-FU) chemotherapy. Studies using human and murine AML cell lines have shown that F10 has strong potency against subtypes of AML with poor clinical prognosis. The focus of these proposed studies is to establish the efficacy of F10 in murine models of relapsed AML, in which AML cells lines are first rendered resistant to standard chemotherapy, and then transplanted into immunocompetent mice. The first aim will evaluate the efficacy of F10 relative to standard treatment in a syngeneic murine model of relapsed AML. The second aim will evaluate the efficacy of F10 relative to standard treatment in primary patient samples of relapsed AML. Primary patient samples will be selected that have common and poor prognostic factors. Demonstrating that F10 is efficacious in the context of these studies will provide the basis for completing pharmacology and toxicology studies necessary for Investigational New Drug (IND) approval, and the advancement of F10 into clinical trials for AML treatment.